A rare variant of African ancestry activates 8q24 lncRNA hub by modulating cancer associated enhancer
| Autor: | Radhakrishnan Sabarinathan, Umer Farooq, Anurag Kumar Singh, Kaivalya Walavalkar, Matthew L. Freedman, Ashwin Nair, Ranveer Singh Jayani, Rajat Mann, Bharath Saravanan, Padubidri V. Shivaprasad, Zubairul Islam, Dimple Notani, Deepanshu Soota, Christopher A. Haiman |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Science General Physics and Astronomy Locus (genetics) Biology Chromatin structure Polymorphism Single Nucleotide General Biochemistry Genetics and Molecular Biology Article Cohort Studies 03 medical and health sciences Prostate cancer 0302 clinical medicine Cancer epigenetics Prostate medicine Humans Genetic Predisposition to Disease Allele Enhancer lcsh:Science Allele frequency Transcription factor Alleles Multidisciplinary Prostatic Neoplasms Functional genomics General Chemistry medicine.disease PVT1 Black or African American 030104 developmental biology medicine.anatomical_structure Enhancer Elements Genetic 030220 oncology & carcinogenesis Cancer research RNA Long Noncoding lcsh:Q Chromosomes Human Pair 8 |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-14 (2020) Nature Communications |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-020-17325-y |
| Popis: | Genetic variation at the 8q24 locus is linked with the greater susceptibility to prostate cancer in men of African ancestry. One such African ancestry specific rare variant, rs72725854 (A>G/T) (~6% allele frequency) has been associated with a ~2-fold increase in prostate cancer risk. However, the functional relevance of this variant is unknown. Here we show that the variant rs72725854 is present in a prostate cancer-specific enhancer at 8q24 locus. Chromatin-conformation capture and dCas9 mediated enhancer blocking establish a direct regulatory link between this enhancer and lncRNAs PCAT1, PRNCR1 and PVT1. The risk allele (‘T’) is associated with higher expression of PCAT1, PVT1 and c-myc in prostate tumors. Further, enhancer with the risk allele gains response to androgen stimulation by recruiting the transcription factor SPDEF whereas, non-risk alleles remain non-responsive. Elevated expression of these lncRNAs and c-myc in risk allele carriers may explain their greater susceptibility to prostate cancer. Genetic variants on chromosome 8q24 are associated with prostate cancer risk in men of African ancestry. Here the authors show that one of these variants, rs72725854 alters the enhancer activity in its region, which upon androgen stimulation, activates multiple oncogenic lncRNAs and c-myc. |
| Databáze: | OpenAIRE |
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